Chronic inflammation is implicated in the etiology of colorectal cancer. Experimental studies have shown that the potent proinflammatory cytokines, namely tumor necrosis factor (TNF)-?, interleukin (IL)-1?, and IL-6, have oncogenic effects. Other cytokines and cytokine receptors, such as soluble TNF receptor types I and II (sTNF-R1 and sTNF-R2), IL-1 receptor antagonist (IL-1Ra), and interferon (IFN)-gamma, are anti-inflammatory and anti-tumor. It is hypothesized that imbalance between the pro- and anti-inflammatory responses, which favors production of the proinflammatory cytokines, is associated with the risk of colorectal cancer. This hypothesis has never been tested in humans. This proposed study will be integrated in an ongoing NIH-funded case-cohort study conducted within the Women's Health Initiative (WHI), a large prospective study of postmenopausal women. The ongoing case-cohort study examines how the risk of breast, endometrial, and colorectal cancers is associated with insulin, IGF-I, estradiol, and adipokines assessed at both serologic and genetic levels. The 500 incident colorectal cancer cases and the 900 subcohort subjects in this case-cohort study will be the subjects of this proposed study, in which (1) plasma levels of proinflammatory cytokines (TNF-?, IL-1?, and IL-6), the anti-tumor IFN-gamma, and anti-inflammatory soluble cytokine receptors (sTNF-R1, sTNF-R2, and IL- 1Ra), and (2) polymorphisms of genes involved in the signal transduction pathways of these cytokines will be examined for their roles in the etiology of colorectal cancer. In addition, combining existing data from the ongoing case-cohort study, we will evaluate the inter- relationships among cytokines, insulin, IGF-I, estrogen, and adipokines as well as explore their interactive effects on the risk of colorectal cancer. The results of this study may help to identify the postmenopausal women who are susceptible to chronic inflammation and tumor development. These high-risk individuals may benefit from prophylactic NSAIDS for prevention of colorectal cancer. This study examines if imbalance between the pro- and anti-inflammatory responses, which favors production of the proinflammatory cytokines, is associated with the risk of colorectal cancer. The results of this study may help to identify the postmenopausal women who are susceptible to chronic inflammation and tumor development. These high-risk individuals may benefit from prophylactic NSAIDS for prevention of colorectal cancer. PUBLIC HEALTH RELEVANCE: This study examines if imbalance between the pro- and anti-inflammatory responses, which favors production of the proinflammatory cytokines, is associated with the risk of colorectal cancer. The results of this study may help to identify the postmenopausal women who are susceptible to chronic inflammation and tumor development. These high-risk individuals may benefit from prophylactic NSAIDS for prevention of colorectal cancer.